Renal manifestations of primary mitochondrial disorders (Review)

  • Authors:
    • Josef Finsterer
    • Fulvio Scorza
  • View Affiliations

  • Published online on: April 12, 2017     https://doi.org/10.3892/br.2017.892
  • Pages:487-494
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations

Abstract

The aim of the present review was to summarize and discuss previous findings concerning renal manifestations of primary mitochondrial disorders (MIDs). A literature review was performed using frequently used databases. The study identified that primary MIDs frequently present as mitochondrial multiorgan disorder syndrome (MIMODS) at onset or in the later course of the MID. Occasionally, the kidneys are affected in MIDs. Renal manifestations of MIDs include renal insufficiency, nephrolithiasis, nephrotic syndrome, renal cysts, renal tubular acidosis, Bartter‑like syndrome, Fanconi syndrome, focal segmental glomerulosclerosis, tubulointerstitial nephritis, nephrocalcinosis, and benign or malign neoplasms. Among the syndromic MIDs, renal involvement has been most frequently reported in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke‑like episodes syndrome, Kearns‑Sayre syndrome, Leigh syndrome and mitochondrial depletion syndromes. Only in single cases was renal involvement also reported in chronic progressive external ophthalmoplegia, Pearson syndrome, Leber's hereditary optic neuropathy, coenzyme‑Q deficiency, X‑linked sideroblastic anemia and ataxia, myopathy, lactic acidosis, and sideroblastic anemia, pyruvate dehydrogenase deficiency, growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death, and hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis syndrome. The present study proposes that the frequency of renal involvement in MIDs is probably underestimated. Diagnosis of renal involvement follows general guidelines and treatment is symptomatic. Thus, renal manifestations of primary MIDs require recognition and appropriate management, as they determine the outcome of MID patients.

Introduction

Depending on the phenotype, mitochondrial disorders (MIDs) are categorised as syndromic or non-syndromic (1). Syndromic MIDs are characterised by recurrent patterns of symptoms and signs, which have the same cause. Many of the syndromic MIDs are known by their acronyms (Table I), although there are a number of syndromic MIDs that have no acronym yet. A characteristic of syndromic MIDs is that they do not affect a single tissue or organ, but involve multiple tissues or organs (2). Multiorgan involvement in MIDs [mitochondrial multiorgan disorder syndrome (MIMODS)] (3) may already be present at onset of the clinical manifestations or may develop during the course of the disease. It appears that MIMODSs evolve as the duration of survival of the patient lengthens. The organs most frequently involved in MIDs are the skeletal muscles, peripheral nerves, central nervous system, eyes, ears, endocrine organs, heart, lungs, gastrointestinal tract, kidneys, bones (including the bone marrow) and the skin. The kidneys are known to be significantly involved in MIDs (47), although, to the best of our knowledge, a current, comprehensive and systemic review regarding kidney disease in MIDs is lacking. Transmission of a MID may follow any type of inheritance. The present review aims to summarise and discuss recent findings concerning phenotype, genotype, pathogenesis, diagnosis, treatment and outcome of kidney disease in MIDs.

Table I.

Renal disease in syndromic MIDs and nsMIDs.

Table I.

Renal disease in syndromic MIDs and nsMIDs.

MIDRFNLNSRCRTABLSTHFSFSGSTINNC
MELASYesNNNNNNYesNN
KSSYesNNNYesYesYesNNYes
MDSNNNNYesNNNNYes
LSNNNYesYesNNNYesN
CPEOYesNNNNNNNNN
PSNNNYesYesNNNNN
LHONNNNNNNNNYesN
PCQDNNYesNNNNYesNN
XLSAYesNNNNNNNNN
GRACILENNNNNNYesNNN
MEGDELYesNNNNNNNNN
HUPRAYesNNNNNNNNN
MLASANNNNYesNNNNN
MSLNNNNYesNNNNN
PDHDNNNNYesNNNNN
nsMIMODSYesYesYesYesYesNNYesYesYes

[i] RF, renal failure; NL, nephrolithiasis; NS, nephrotic syndrome; RC, renal cysts; RTA, renal tubular acidosis; BLS, Bartter-like syndrome; TDFS, Toni-Debré-Fanconi syndrome; FSGS, focal segmental glomerulosclerosis; TIN, tubulo-interstitial nephritis (nephrophthisis); NC, nephrocalcinosis; LS, Leigh syndrome; PCQD, primary coenzyme-Q deficiency; XLSA, X-linked sideroblastic anemia; nsMIMODS, non-specific MIMODS; N, not reported.

Methods

Data for the present review were identified by searching Medical Literature Analysis and Retrieval System Online (MEDLINE; https://www.ncbi.nlm.nih.gov/pubmed), Current Contents (http://wokinfo.com/products_tools/multidisciplinary/CCC/), Excerpta Medica database (EMBASE; https://www.embase.com/login), Web of Science (https://login.webofknowledge.com/error/Error?PathInfo=%2F&Alias=WOK5&Domain=.webofknowledge.com&Src=IP&RouterURL=https%3A%2F%2Fwww.webofknowledge.com%2F&Error=IPError), Web of Knowledge (https://de.slideshare.net/davehirsty/science-citation-index), Latin American and Caribbean Health Sciences Literature (LILACS; http://bases.bireme.br/cgi-bin/wxislind.exe/iah/online/?IsisScript=iah/iah.xis&base=LILACS&lang=i&form=F), bibliographic database for science (SCOPUS; https://www.scopus.com/) and Google Scholar (https://scholar.google.de) for references to relevant articles using the following search terms: ‘Kidney’, ‘renal’, ‘renal insufficiency’, ‘nephrolithiasis’, ‘nephrocalcinosis’, ‘renal cysts’, ‘Bartter-like syndrome’, ‘Fanconi syndrome’, ‘Toni-Debré-Fanconi syndrome’, ‘nephrotic syndrome’, ‘tubulointerstitial nephritis’, and ‘renal tubular acidosis’ in combination with all acronyms for syndromic MIDs and the terms ‘mtDNA’, ‘respiratory chain’, ‘electron transport’, ‘mitochondrion’, and ‘mitochondrial’. Randomised (blinded or open label) clinical trials and observational studies (longitudinal studies, case series and case reports) were considered. Abstracts and reports from meetings were not included. Only articles in English, French, Spanish or German, and those published between 1966 and 2016 were considered. Appropriate papers were evaluated and discussed for their usefulness to be incorporated in the review. Reference lists of the appropriate papers were reviewed for further articles matching the search terms. A paper was included if it reported a single patient or a cohort of patients with MIDs who also manifested with any type of primary or secondary kidney disease.

Results

Classification

Renal disease in MIDs may be classified as primary or secondary. Secondary kidney disease may result from primary involvement of organs other than the kidneys in the MID. In the case of cardiac involvement in MID, there may be renal infarction from atrial fibrillation or heart failure, or hypertensive kidney disease from mitochondrial arterial hypertension. In the case of mitochondrial diabetes, renal insufficiency may be a consequence of the primary involvement of the pancreas in the MID. Another secondary renal disorder due to a primary mitochondrial defect may be renal insufficiency from rhabdomyolysis due to mitochondrial myopathy or mitochondrial epilepsy (8). Primary renal manifestations of MIDs include acute or chronic renal failure, nephrolithiasis, nephrotic syndrome, renal cysts, renal tubular acidosis (RTA), Bartter-like syndrome, Toni-Debré-Fanconi syndrome (TDFS), focal segmental glomerulosclerosis (FSGS), tubulointerstitial nephritis (TIN), nephrocalcinosis, and benign or malignant neoplasms (9). Renal involvement in MIDs may be classified according to the number of organs that are affected in addition to the kidney. If no other organs are additionally involved (absence of MIMODS) the mitochondrial nature of renal disease is often difficult to detect (10). However, when more organs are affected, it is more suggestive of a MID. Additionally, renal involvement may be classified according to the priority within the phenotype. In certain cases, renal involvement may dominate the phenotype whereas in other cases, renal disease may be a non-dominant feature. A further differentiation of renal involvement in MIDs relies on whether the underlying genotype manifests clinically or remains subclinical. Subclinical involvement may be detected upon observation of morphological abnormalities of mitochondria and a high quantity of heteroplasmy of mutated mtDNA during kidney biopsy or autopsy (11,12).

Renal disease in syndromic MIDs

Renal involvement has been reported in a number of syndromic MIDs, which predominantly include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns Sayre syndrome (KSS; Table II) (13,14) and mitochondrial depletion syndromes (MDSs). On rare occasions, renal disease may be found in other rarer types of syndromic MIDs.

Table II.

Renal dysfunction in Kearns Sayre syndrome.

Table II.

Renal dysfunction in Kearns Sayre syndrome.

Renal abnormalityPatients, nAge, yearsSexRefs.
Renal insufficiency110m78
4range, 6–21f, 1; m, 379
1NANA80
Renal tubular acidosis17m32
118f33
Bartter-like syndrome114m13
17f35
110m34
Toni-Debré-Fanconi syndrome111f15
110m27
110m28
15m29
118m30
18f31
143f14
113f26

[i] f, female; m, male; NA, not accessible.

MELAS

MELAS is one of the syndromic MIDs in which renal disease is fairly frequent. In a 14-year-old female with MELAS syndrome, the initial manifestation of the MID was an FSGS, which occurred 3 years prior to diagnosis of the MID (15). In a 35-year-old female with MELAS syndrome resulting from the m.13513G>A mutation, renal failure was the initial manifestation of the MID 9 years before diagnosis of the MID (10). In a 50-year-old male with MELAS syndrome, chronic renal failure requiring hemodialysis was one of the clinical manifestations (16). Chronic renal failure was the indication for renal transplantation in a 58-year-old male with MELAS syndrome (17). In a 13-year-old Asian female with MELAS syndrome, renal involvement manifested as FSGS (18). In another MELAS patient acute renal failure occurred and was associated with severe hyponatriemia due to renal sodium loss (19). Furthermore, in a female MELAS syndrome patient, severe kidney involvement with changes of FSGS was reported (20). Acute or chronic renal failure has been also reported in a number of MELAS patients with or without diabetes, suggesting that renal dysfunction is primary or secondary (21). In a series of 5 MELAS patients, FSGS was a phenotypic feature in all of them; thus, the authors concluded that renal involvement in MELAS may be underestimated (7). Chronic renal failure appears to be a typical manifestation of MELAS (22) and FSGS may be the dominant feature in these patients (23). Kidney cancer was reported in a 41-year-old male who was exhibiting MELAS syndrome (24). A histological work-up additionally revealed arteriolonephrosclerosis (24) and renal cell carcinoma was reported in a 2-year-old male with MELAS syndrome (25).

KSS

Renal abnormalities so far described in KSS include renal failure, RTA, Bartter-like syndrome and TDFS (Table II). In an 11-year-old female with KSS, TDFS was diagnosed 8 years prior to the diagnosis of the MID (15). TDFS was also reported in a 13-year-old female with KSS who additionally manifested with anhidrosis (26), as well as other patients (14,2731). In a 5-year-old male with KSS, the MID manifested with RTA (Table II) (32), which was also described in an 18-year-old female (Table II) (33). In a 10-year-old male with KSS, the MID manifested in the kidneys as renal tubular dysfunction with isosthenuria, decreased urine-concentrating ability, and excessive excretion of potassium and magnesium (34). In addition, hyperreninemia and hyperaldosteronism were present in the absence of arterial hypertension, resulting in a diagnosis of Bartter-like syndrome (34). Furthermore, Bartter-like syndrome has been described in two other patients with KSS, in a 14-year-old male (13) and a 7-year-old female (Table II) (35). In addition, nephrocalcinosis has been identified as a rare feature of KSS (13).

MDS

MDSs are characterised by a reduction in the quantity of mtDNA within a mitochondrion of a cell. MDSs are due to mutations in the ribonucleotide reductase regulatory TP53 inducible subunit M2B (RRM2B), MpV17 mitochondrial inner membrane protein (MPV17), DNA polymerase γ, catalytic subunit (POLG1), DNA polymerase γ 2, accessory subunit (POLG2), succinate-CoA ligase ADP-forming β subunit (SUCLA2), succinate-CoA ligase GDP-forming β subunit (SUCLG2), twinkle mtDNA helicase (C10orf2), deoxyguanosine kinase (DGUOK), thymidine kinase 2, mitochondrial (TK2), F-box and leucine rich repeat protein 4 (FBXL4), and transcription factor A, mitochondrial (TFAM) genes, In an infant with MDS due to a mutation in the RRM2B gene, the MID manifested along with proximal renal tubulopathy and nephrocalcinosis (36). In an infant with MDS, but without detection of the underlying genetic defect, RTA developed 1 year after liver transplantation and was attributed to tacrolimus toxicity and renal involvement in the MID (37). In three siblings with MDS due to a C10orf2 (twinkle) mutation, the MDS manifested as hepatocerebral syndrome and as proximal renal tubulopathy (Table III) (38). Renal tubulopathy was also reported in a female newborn with MDS carrying an mtDNA copy number of only 2% (39). In one of two males with MDS due to a mutation in the RRM2B gene, proximal renal tubulopathy was described (40). Tubulopathy was also present in a female infant with MDS carrying the RRM2B mutation c.368T>C (41). In addition, tubulopathy was detected in three patients during an investigation of 11 patients with MDS due to mutations in the DGUOK gene (42). Furthermore, MDS resulting from mutations in the MPV17 gene may be associated with tubulopathy (Table III) (43).

Table III.

Genes in which mutations cause MID with renal involvement.

Table III.

Genes in which mutations cause MID with renal involvement.

Mutated geneRenal diseaseRefs.
mtDNA
  tRNA(Leu)RF, FSGS(16,81)
  tRNA(Phe)Tubulointerstitial fibrosis, RF, TDFS(74,82)
  tRNA(Tyr)FSGS, nephrotic syndrome(75)
  tRNA(Ser)Proteinurea, glomerulosclerosis(66)
  COXIIIRF(83)
nDNA
  COX10Tubulopathy(65)
  SURF1RTA(48)
  BCS1LProximal tubulopathy(68)
  UQCC1Tubulopathy(72)
  TMEM70RTA, RF, hydronephrosis(69)
  MRPS22Tubulopathy(71)
  YARS2Tubulopathy(53)
  SARS2Tubulopathy(49)
  RRM2BProximal tubulopathy, NC(36,40,41,84)
  TWINKLEProximal tubulopathy(38)
  MPV17Tubulopathy(43)
  DGUOKTubulopathy(42)
  LARS2RF(70)
  RMND1Chronic RF(73)
  ACAD9Megamitochondria in tubules(54)
  CLPBNephrocalcinosis, cysts, aciduria(85)
  ADCK4Nephrotic syndrome(77,78)
  MRPL44Renal failure(86)

[i] RF, renal failure; RTA, renal tubular acidosis; NC, nephrocalcinosis.

Other syndromic MIDs with renal involvement

Single cases of renal involvement have been reported in other syndromic MIDs, such as chronic progressive external ophthalmoplegia (CPEO) (44), Pearson syndrome (45), Leber hereditary optic neuropathy (LHON) (46), coenzyme-Q deficiency, X-linked sideroblastic anemia (XLSA) (47), Leigh syndrome (48), or hyperuricemia, metabolic alkalosis, pulmonary hypertension, and progressive renal failure in infancy (HUPRA) syndrome (49). In a 44-year-old female with CPEO, the MID initially manifested initially with hearing loss at age 22 years, which was followed by renal failure at 30 years of age (44). In an infant with Pearson syndrome due to a single mtDNA deletion, the bone marrow, central nervous system, exocrine pancreas and the kidneys were involved. Renal involvement manifested as severe tubular dysfunction (45). In another patient with Pearson syndrome multiple renal cysts were reported (50). In a 1-year-old female with LHON, renal involvement manifested as nephronophthisis, also referred to as TIN (46). In an infant with primary coenzyme-Q deficiency due to a mutation in the COQ2 gene, the MID manifested with nephrotic syndrome due to FSGS (51). In an 81-year-old male with XLSA due to mutations in the ALAS2 gene, renal involvement manifested as severe renal failure requiring haemodialysis (47). In a study of four patients with Leigh syndrome due to a mutation in the SURF1 gene, three had significant proximal RTA (48). Hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis (HUPRA) syndrome due to SARS2 gene mutations is, by definition, a rare MID that presents along with renal failure (52). In two Palestinian infants with HUPRA syndrome due to a SARS2 mutation, tubulopathy was a cardinal phenotypic feature of the disease (49). In a Turkish family with myopathy, lactic acidosis, and sideroblastic anaemia (MLASA) syndrome due to a YARS2 mutation, renal involvement manifested as tubulopathy (53). In a neonate with Leigh syndrome due to a mutation in the ACAD9 gene, autopsy revealed hyperplasia of mitochondria in renal tubular cells (54). In addition, in a patient with Leigh syndrome due to a mutation in the ND5 gene renal salt loss was deemed responsible for secondary hyponatriemia (55). Diffuse glomerulocystic kidneys were reported in a patient with Leigh syndrome, but without detecting the genetic defect (56). Growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE) syndrome is an early-onset, autosomal recessive multisystem MID due to mutations in the BCS1L gene. Clinically, GRACILE syndrome is characterised by fetal growth retardation, Fanconi-type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early mortality (57). One of the clinical hallmarks of GRACILE syndrome is TDFS-type tubulopathy with aminoaciduria. In a mouse model of GRACILE syndrome, tubulopathy was one of various other phenotypic features (58). Late-onset nephrotic syndrome was described in Mpv17 knock-out mice (59). In single patients with multiple systemic lipomatosis, which may be due to the m.8344A>G mutation, RTA has been reported (60). In a male infant with pyruvate dehydrogenase deficiency (PDH), RTA was one of the clinical manifestations in addition to lactic acidosis, contributing to the death of this individual (61). Whether renal excretion of urinary phosphatidylethanolamine, cardiolipin, and phosphatidylserine in four patients with myoclonus epilepsy with ragged-red fibres (MERRF) (62) and in one patient with CPEO was truly attributable to renal involvement remains unknown, but they may be derived from sulfatides, which are specific to the kidneys (62).

Renal disease in non-specific syndromic MIDs

In four adult patients with FSGS, kidney disease was attributed to an MID, as renal biopsy revealed the presence of the m.3243A>G mutation in the tRNA(Leu) gene (61). Notably, no other organs were affected in these four patients; thus, kidney disease was the initial manifestation and dominant feature of the MID and, therefore, the phenotype was not consistent with MELAS syndrome at the time of diagnosis (63). In a patient with sensorineural blindness, attributed to a non-genetically proven MID, Bartter-like syndrome was the second phenotypic feature (64). In a consanguineous family with isolated COX-deficiency due to a mutation in the COX10 gene, which encodes the heme A:farnesyltransferase, increased urinary amino acids suggested proximal renal tubulopathy (65). In a 54-year-old female, the homoplasmic m.7501T>A mutation in the tRNA(Ser) gene manifested as proteinurea due to sclerosis of one-quarter of the glomeruli observed during kidney biopsy (66). Almost one-third of the interstitium was fibrotic in this patient. Tubular granular swollen epithelial cells (GSECs), which have been demonstrated to indicate a MID (67), were present in the medulla collecting ducts (66). In a study of six patients with encephalopathy, hepatopathy, and proximal tubulopathy, the causative mutation was detected in the BCS1L gene resulting in respiratory chain complex III deficiency (68). In a study of 35 multi-ethnic patients carrying a TMEM70 mutation, 35% manifested with renal disease in the form of RTA, hydronephrosis and acute or chronic renal failure (69). In a newborn girl with MIMODS due to a mutation in the LARS2 gene, encoding for a mitochondrial amino-acyl-tRNA synthetase, progressive renal failure was responsible for mortality 5 days after birth (70). In three children from the same consanguineous parents, antenatal skin oedema, hypotonia, cardiomyopathy and tubulopathy were attributed to mutations in the MRPS22 gene (71). In a consanguineous Lebanese patient with respiratory chain complex III deficiency due to a UQCC2 gene mutation, renal tubulopathy was one of the phenotypic manifestations, in addition to severe intrauterine growth retardation and neonatal lactic acidosis (72). Chronic renal failure was also reported in an 11-month-old male who presented with truncal ataxia, sensorineural hearing loss, muscle hypotonia, delayed visual maturation, global developmental delay and dilated cardiomyopathy (73). Nuclear genetic studies identified a causative mutation in the RMND1 gene (73). End-stage renal disease due to TIF was reported in a 16-month-old girl with developmental regression, lactic acidosis, hypotonia, gastrointestinal dysmotility, adrenal insufficiency, arterial hypertension and haematological abnormalities carrying a tRNA(Phe) mutation (74). Isolated renal disease as the sole manifestation of a MID was reported in a 9-year-old female with steroid-resistant FSGS (75). The MID was due to a point mutation in the mtDNA located at the tRNA(Tyr) gene (75).

Diagnosis

A diagnostic work-up of renal disease in MIDs is not different from a work-up of renal disease in patients without an MID. The diagnosis is based on blood tests, urine analysis, imaging, functional tests and biopsies. Biopsy is important, as it may show abnormalities, which have been reported in MID patients with renal involvement (Table I), as well as morphological abnormalities of mitochondria. A strong indicator for the mitochondrial nature of a kidney disease appears to be the presence of GSECs. MID patients with suspected renal involvement should, therefore, undergo kidney biopsy, to establish whether GSECs are present. In addition, a biopsy may show microvascular degeneration of the renal tubular epithelial cells, such as in Leigh syndrome. If additional biochemical investigations are performed, dysfunction of one or various respiratory chain complexes may be detected. If genetic studies are conducted, mutations in mtDNA- or nDNA-located genes may be detected (Table III) and, in the case of mtDNA mutations, the heteroplasmy rates may be determined. Notably, a single patient may present with more than one renal abnormality (Table I).

Treatment

Treatment of mitochondrial nephropathy is the same as for non-mitochondrial nephropathy. However, drugs that are mitochondrion-toxic should generally be avoided in MID patients. Though not supported by evidence from appropriate clinical trials, mitochondrial nephropathy may respond to supportive treatment administered to MID patients, such as antioxidants, co-factors or vitamins (76). In patients with steroid resistant nephrotic syndrome due to mutations in the ADCK4 gene, which is involved in COQ10 biosynthesis, coenzyme-Q may be highly beneficial (77). Renal failure in MIDs may be of such a degree that haemodialysis may be required.

Outcome

To the best of our knowledge, there are no available systematic studies regarding the outcome of renal disease in MIDs. The outcome of renal involvement in MIDs is dependent on the underlying mutation, as well as the type of renal disease. The outcome of renal disease in MIDs is also dependent on whether it is primary or secondary. In the case of mtDNA mutations, the heteroplasmy rate in the kidneys may be significant for the outcome of renal disease. Though not systematically investigated, it is speculated that the severity of renal disease increases and that the outcome of kidney disease becomes worse as the heteroplasmy rate increases.

Conclusion

The present review demonstrates that renal involvement in MIDs is more frequent than originally anticipated, and that primary and secondary renal involvement in MIDs occurs in syndromic and non-syndromic MIDs. Among the syndromic MIDs renal involvement has been most frequently reported in MELAS syndrome, KSS and MDS. Only rarely was renal involvement described in patients with CPEO, Pearson syndrome, LHON, primary coenzyme-Q deficiency, XLSA, Leigh syndrome, PDH deficiency, GRACILE syndrome HUPRA syndrome, or non-specific syndromic MIDs. Primary renal involvement in MIDs includes renal failure, nephrolithiasis, nephrotic syndrome, renal cysts, renal tubular acidosis, Bartter-like syndrome, Fanconi syndrome, FSGS, TIN, nephrocalcinosis and neoplasms. Bartter-like syndrome is characterised by a hyperreninemic hyperaldosteronism, hyponatriemia, hypokaliemia, hypo-osmolarity, arterial hypotension despite hyperreninemic hyperaldosteronism and alkalosis.

Diagnosis of renal involvement in MIDs is the same as diagnosing renal disease in non-MID patients. In MID patients with a Bartter-like syndrome, Bartter syndrome must be excluded by showing absence of a mutation in the SLC12A1 (type 1), KCNJ1 (type 2), ClCNKb (type 3), BSND (type 4), or the CSAR gene (type 5). If mitochondrial nephropathy is the initial manifestation of an MID, diagnosing the MID may be delayed unless genetic or biochemical investigations are performed with renal biopsies. In particular, patients with one of the frequent renal manifestations of MID should be closely followed up for establishing whether organs other than the kidneys have been affected, and first-degree relatives must be thoroughly investigated for MID. Treatment of renal disease in MIDs follows general guidelines, however, physicians must be wary of prescribing mitochondrion-toxic compounds, which could worsen renal disease and involvement of other organs in MIDs. Antioxidants, vitamins, and other co-factors may be of additional benefit for renal disease in MIDs, but, to the best of our knowledge, no systematic studies have been performed addressing these issues. The focus of future research in MIDs should be directed towards mitochondrial nephropathy, and optimized diagnostic and therapeutic procedures must be established. From a translational perspective, animal models may provide important mechanistic insights into MIDs and may be particularly useful for the development of novel compounds for improving the therapeutic options in MIDs.

Glossary

Abbreviations

Abbreviations:

CPEO

chronic progressive external ophthalmoplegia

FSGS

focal segmental glomerulosclerosis

GRACILE

growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death

GSECs

granular swollen epithelial cells

HUPRA

hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis

KSS

Kearns-Sayre syndrome

LHON

Leber's hereditary optic neuropath

MDS

mitochondrial depletion syndrome

MELAS

mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

MERRF

myoclonus epilepsy with ragged-red fibers

MID

mitochondrial disorder

MIMODS

mitochondrial multi-organ disorder syndrome

MLASA

myopathy, lactic acidosis, and sideroblastic anemia

mtDNA

mitochondrial deoxyribonucleic acid

RTA

renal tubular acidosis

TDFS

Toni-Debré-Fanconi syndrome

TIN

tubulointerstitial nephritis

XLSA

X-linked sideroblastic anemia

References

1 

Finsterer J: Inherited mitochondrial disorders. Adv Exp Med Biol. 942:187–213. 2012. View Article : Google Scholar : PubMed/NCBI

2 

McFarland R, Taylor RW and Turnbull DM: A neurological perspective on mitochondrial disease. Lancet Neurol. 9:829–840. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Finsterer J and Zarrouk-Mahjoub S: Mitochondrial Disorders May Mimic Amyotrophic Lateral Sclerosis at Onset. Sultan Qaboos Univ Med J. 16:e92–e95. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Emma F, Montini G, Parikh SM and Salviati L: Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat Rev Nephrol. 12:267–280. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Niaudet P: Renal involvement in mitochondrial cytopathies. Nephrol Ther. 9:116–124. 2013.(In French). View Article : Google Scholar : PubMed/NCBI

6 

Emma F, Bertini E, Salviati L and Montini G: Renal involvement in mitochondrial cytopathies. Pediatr Nephrol. 27:539–550. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Seidowsky A, Hoffmann M, Glowacki F, Dhaenens CM, Devaux JP, de Sainte Foy CL, Provot F, Gheerbrant JD, Hummel A, Hazzan M, et al: Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature. Clin Nephrol. 80:456–463. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Yokoyama J, Yamaguchi H, Shigeto H, Uchiumi T, Murai H and Kira J: A case of rhabdomyolysis after status epilepticus without stroke-like episodes in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Rinsho Shinkeigaku. 56:204–207. 2016.(In Japanese). View Article : Google Scholar : PubMed/NCBI

9 

Finsterer J and Frank M: Prevalence of neoplasms in definite and probable mitochondrial disorders. Mitochondrion. 29:31–34. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Motoda A, Kurashige T, Sugiura T, Nakamura T, Yamawaki T, Arihiro K and Matsumoto M: A case of MELAS with G13513A mutation presenting with chronic kidney disease long before stroke-like episodes. Rinsho Shinkeigaku. 53:446–451. 2013.(In Japanese). View Article : Google Scholar : PubMed/NCBI

11 

Ponzetto C, Bresolin N, Bordoni A, Moggio M, Meola G, Bet L, Prelle A and Scarlato G: Kearns-Sayre syndrome: Different amounts of deleted mitochondrial DNA are present in several autoptic tissues. J Neurol Sci. 96:207–210. 1990. View Article : Google Scholar : PubMed/NCBI

12 

Bresolin N, Moggio M, Bet L, Gallanti A, Prelle A, Nobile-Orazio E, Adobbati L, Ferrante C, Pellegrini G and Scarlato G: Progressive cytochrome c oxidase deficiency in a case of Kearns-Sayre syndrome: Morphological, immunological, and biochemical studies in muscle biopsies and autopsy tissues. Ann Neurol. 21:564–572. 1987. View Article : Google Scholar : PubMed/NCBI

13 

Emma F, Pizzini C, Tessa A, Di Giandomenico S, Onetti-Muda A, Santorelli FM, Bertini E and Rizzoni G: ‘Bartter-like’ phenotype in Kearns-Sayre syndrome. Pediatr Nephrol. 21:355–360. 2006. View Article : Google Scholar : PubMed/NCBI

14 

Berio A and Piazzi A: Kearns-Sayre syndrome associated with de Toni-Debré-Fanconi syndrome due to cytochrome-c-oxidase (COX) deficiency. Panminerva Med. 43:211–214. 2001.PubMed/NCBI

15 

Mochizuki H, Joh K, Kawame H, Imadachi A, Nozaki H, Ohashi T, Usui N, Eto Y, Kanetsuna Y and Aizawa S: Mitochondrial encephalomyopathies preceded by de-Toni-Debré-Fanconi syndrome or focal segmental glomerulosclerosis. Clin Nephrol. 46:347–352. 1996.PubMed/NCBI

16 

Mima A, Shiota F, Matsubara T, Iehara N, Akagi T, Abe H, Nagai K, Matsuura M, Murakami T, Kishi S, et al: An autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with intestinal bleeding in chronic renal failure. Ren Fail. 33:622–625. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Lederer SR, Klopstock T and Schiffl H: MELAS: A mitochondrial disorder in an adult patient with a renal transplant. Wien Klin Wochenschr. 122:363–365. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Lau KK, Yang SP, Haddad MN, Butani L and Makker SP: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes syndrome with hypothyroidism and focal segmental glomerulosclerosis in a paediatric patient. Int Urol Nephrol. 39:941–946. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Kubota H, Tanabe Y, Takanashi J and Kohno Y: Episodic hyponatremia in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). J Child Neurol. 20:116–120. 2005. View Article : Google Scholar : PubMed/NCBI

20 

Cheong HI, Chae JH, Kim JS, Park HW, Ha IS, Hwang YS, Lee HS and Choi Y: Hereditary glomerulopathy associated with a mitochondrial tRNA(Leu) gene mutation. Pediatr Nephrol. 13:477–480. 1999. View Article : Google Scholar : PubMed/NCBI

21 

Iwasaki N, Babazono T, Tsuchiya K, Tomonaga O, Suzuki A, Togashi M, Ujihara N, Sakka Y, Yokokawa H, Ogata M, et al: Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene in Japanese patients with diabetes mellitus and end stage renal disease. J Hum Genet. 46:330–334. 2001. View Article : Google Scholar : PubMed/NCBI

22 

Yanagihara C, Oyama A, Tanaka M, Nakaji K and Nishimura Y: An autopsy case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome with chronic renal failure. Intern Med. 40:662–665. 2001. View Article : Google Scholar : PubMed/NCBI

23 

Kurogouchi F, Oguchi T, Mawatari E, Yamaura S, Hora K, Takei M, Sekijima Y, Ikeda S and Kiyosawa K: A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with severe focal-segmental glomerulosclerosis as main clinical manifestation. Am J Nephrol. 18:551–556. 1998. View Article : Google Scholar : PubMed/NCBI

24 

Piccoli GB, Bonino LD, Campisi P, Vigotti FN, Ferraresi M, Fassio F, Brocheriou I, Porpiglia F and Restagno G: Chronic kidney disease, severe arterial and arteriolar sclerosis and kidney neoplasia: On the spectrum of kidney involvement in MELAS syndrome. BMC Nephrol. 13:92012. View Article : Google Scholar : PubMed/NCBI

25 

Sangkhathat S, Kusafuka T, Yoneda A, Kuroda S, Tanaka Y, Sakai N and Fukuzawa M: Renal cell carcinoma in a pediatric patient with an inherited mitochondrial mutation. Pediatr Surg Int. 21:745–748. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Mori K, Narahara K, Ninomiya S, Goto Y and Nonaka I: Renal and skin involvement in a patient with complete Kearns-Sayre syndrome. Am J Med Genet. 38:583–587. 1991. View Article : Google Scholar : PubMed/NCBI

27 

Ho J, Pacaud D, Rakic M and Khan A: Diabetes in pediatric patients with Kearns-Sayre syndrome: Clinical presentation of 2 cases and a review of pathophysiology. Can J Diabetes. 38:225–228. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Liu HM, Tsai LP, Chien YH, Wu JF, Weng WC, Peng SF, Wu ET, Huang PH, Lee WT, Tsai IJ, et al: A novel 3670-base pair mitochondrial DNA deletion resulting in multi-systemic manifestations in a child. Pediatr Neonatol. 53:264–268. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Tzoufi M, Makis A, Chaliasos N, Nakou I, Siomou E, Tsatsoulis A, Zikou A, Argyropoulou M, Bonnefont JP and Siamopoulou A: A rare case report of simultaneous presentation of myopathy, Addison's disease, primary hypoparathyroidism, and Fanconi syndrome in a child diagnosed with Kearns-Sayre syndrome. Eur J Pediatr. 172:557–561. 2013. View Article : Google Scholar : PubMed/NCBI

30 

Mihai CM, Catrinoiu D, Toringhibel M, Stoicescu RM and Hancu A: De Toni-Debré-Fanconi syndrome in a patient with Kearns-Sayre syndrome: A case report. J Med Case Reports. 3:1012009. View Article : Google Scholar

31 

Pitchon EM, Cachat F, Jacquemont S, Hinard C, Borruat FX, Schorderet DF, Morris MA and Munier FL: Patient with Fanconi Syndrome (FS) and retinitis pigmentosa (RP) caused by a deletion and duplication of mitochondrial DNA (mtDNA). Klin Monatsbl Augenheilkd. 224:340–343. 2007. View Article : Google Scholar : PubMed/NCBI

32 

Eviatar L, Shanske S, Gauthier B, Abrams C, Maytal J, Slavin M, Valderrama E and DiMauro S: Kearns-Sayre syndrome presenting as renal tubular acidosis. Neurology. 40:1761–1763. 1990. View Article : Google Scholar : PubMed/NCBI

33 

Katsanos KH, Elisaf M, Bairaktari E and Tsianos EV: Severe hypomagnesemia and hypoparathyroidism in Kearns-Sayre syndrome. Am J Nephrol. 21:150–153. 2001. View Article : Google Scholar : PubMed/NCBI

34 

Goto Y, Itami N, Kajii N, Tochimaru H, Endo M and Horai S: Renal tubular involvement mimicking Bartter syndrome in a patient with Kearns-Sayre syndrome. J Pediatr. 116:904–910. 1990. View Article : Google Scholar : PubMed/NCBI

35 

Choe Y, Park E, Hyun HS, Ko JM, Kang HG, Kim JH, Park SH and Cheong HI: A 7-year-old girl presenting with a Bartter-like phenotype: Answers. Pediatr Nephrol. (In press).

36 

Stojanovic V, Mayr JA, Sperl W, Barišić N, Doronjski A and Milak G: Infantile peripheral neuropathy, deafness, and proximal tubulopathy associated with a novel mutation of the RRM2B gene: Case study. Croat Med J. 54:579–584. 2013. View Article : Google Scholar : PubMed/NCBI

37 

De Greef E, Christodoulou J, Alexander IE, Shun A, O'Loughlin EV, Thorburn DR, Jermyn V and Stormon MO: Mitochondrial respiratory chain hepatopathies: Role of liver transplantation. A case series of five patients. JIMD Rep. 4:5–11. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Prasad C, Melançon SB, Rupar CA, Prasad AN, Nunez LD, Rosenblatt DS and Majewski J: Exome sequencing reveals a homozygous mutation in TWINKLE as the cause of multisystemic failure including renal tubulopathy in three siblings. Mol Genet Metab. 108:190–194. 2013. View Article : Google Scholar : PubMed/NCBI

39 

Lee IC, Lee NC, Lu JJ and Su PH: Mitochondrial depletion causes neonatal-onset leigh syndrome, myopathy, and renal tubulopathy. J Child Neurol. 28:404–408. 2013. View Article : Google Scholar : PubMed/NCBI

40 

Kollberg G, Darin N, Benan K, Moslemi AR, Lindal S, Tulinius M, Oldfors A and Holme E: A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion. Neuromuscul Disord. 19:147–150. 2009. View Article : Google Scholar : PubMed/NCBI

41 

Acham-Roschitz B, Plecko B, Lindbichler F, Bittner R, Mache CJ, Sperl W and Mayr JA: A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy. Mol Genet Metab. 98:300–304. 2009. View Article : Google Scholar : PubMed/NCBI

42 

Dimmock DP, Zhang Q, Dionisi-Vici C, Carrozzo R, Shieh J, Tang LY, Truong C, Schmitt E, Sifry-Platt M, Lucioli S, et al: Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase. Hum Mutat. 29:330–331. 2008. View Article : Google Scholar : PubMed/NCBI

43 

El-Hattab AW and Scaglia F: Mitochondrial DNA depletion syndromes: Review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics. 10:186–198. 2013. View Article : Google Scholar : PubMed/NCBI

44 

Yuri T, Kondo Y, Kohno K, Lei YC, Kanematsu S, Kuwata M, Iwasaka T and Tsubura A: An autopsy case of chronic progressive external ophthalmoplegia with renal insufficiency. Med Mol Morphol. 41:233–237. 2008. View Article : Google Scholar : PubMed/NCBI

45 

Majander A, Suomalainen A, Vettenranta K, Sariola H, Perkkiö M, Holmberg C and Pihko H: Congenital hypoplastic anemia, diabetes, and severe renal tubular dysfunction associated with a mitochondrial DNA deletion. Pediatr Res. 30:327–330. 1991. View Article : Google Scholar : PubMed/NCBI

46 

Singh V, Bhattacharjee S, Singh K and Narula MK: Leber's amaurosis with nephronophthisis and congenital hepatic fibrosis. Indian Pediatr. 41:1053–1056. 2004.PubMed/NCBI

47 

Furuyama K, Harigae H, Kinoshita C, Shimada T, Miyaoka K, Kanda C, Maruyama Y, Shibahara S and Sassa S: Late-onset X-linked sideroblastic anemia following hemodialysis. Blood. 101:4623–4624. 2003. View Article : Google Scholar : PubMed/NCBI

48 

Tay SK, Sacconi S, Akman HO, Morales JF, Morales A, De Vivo DC, Shanske S, Bonilla E and DiMauro S: Unusual clinical presentations in four cases of Leigh disease, cytochrome C oxidase deficiency, and SURF1 gene mutations. J Child Neurol. 20:670–674. 2005. View Article : Google Scholar : PubMed/NCBI

49 

Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, Segel R, Elpeleg O, Nassar S and Frishberg Y: Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet. 88:193–200. 2011. View Article : Google Scholar : PubMed/NCBI

50 

Gürgey A, Ozalp I, Rötig A, Coşkun T, Tekinalp G, Erdem G, Akeören Z, Caglar M and Bakkaloglu A: A case of Pearson syndrome associated with multiple renal cysts. Pediatr Nephrol. 10:637–638. 1996. View Article : Google Scholar : PubMed/NCBI

51 

Scalais E, Chafai R, Van Coster R, Bindl L, Nuttin C, Panagiotaraki C, Seneca S, Lissens W, Ribes A, Geers C, et al: Early myoclonic epilepsy, hypertrophic cardiomyopathy and subsequently a nephrotic syndrome in a patient with CoQ10 deficiency caused by mutations in para-hydroxybenzoate-polyprenyl transferase (COQ2). Eur J Paediatr Neurol. 17:625–630. 2013. View Article : Google Scholar : PubMed/NCBI

52 

Rivera H, Martín-Hernández E, Delmiro A, García-Silva MT, Quijada-Fraile P, Muley R, Arenas J, Martín MA and Martínez-Azorín F: A new mutation in the gene encoding mitochondrial seryl-tRNA synthetase as a cause of HUPRA syndrome. BMC Nephrol. 14:1952013. View Article : Google Scholar : PubMed/NCBI

53 

Nakajima J, Eminoglu TF, Vatansever G, Nakashima M, Tsurusaki Y, Saitsu H, Kawashima H, Matsumoto N and Miyake N: A novel homozygous YARS2 mutation causes severe myopathy, lactic acidosis, and sideroblastic anemia 2. J Hum Genet. 59:229–232. 2014. View Article : Google Scholar : PubMed/NCBI

54 

Leslie N, Wang X, Peng Y, Valencia CA, Khuchua Z, Hata J, Witte D, Huang T and Bove KE: Neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules. Hum Pathol. 49:27–32. 2016. View Article : Google Scholar : PubMed/NCBI

55 

Brecht M, Richardson M, Taranath A, Grist S, Thorburn D and Bratkovic D: Leigh Syndrome Caused by the MT-ND5 m.13513G>A Mutation: A Case Presenting with WPW-Like Conduction Defect, Cardiomyopathy, Hypertension and Hyponatraemia. JIMD Rep. 19:95–100. 2015. View Article : Google Scholar : PubMed/NCBI

56 

Yamakawa T, Yoshida F, Kumagai T, Watanabe H, Takano A, Mizuno M, Ikeguchi H, Morita Y, Sobue G and Matsuo S: Glomerulocystic kidney associated with subacute necrotizing-encephalomyelopathy. Am J Kidney Dis. 37:E142001. View Article : Google Scholar : PubMed/NCBI

57 

Kasapkara ÇS, Tümer L, Ezgü FS, Küçükçongar A and Hasanoğlu A: BCS1L gene mutation causing GRACILE syndrome: Case report. Ren Fail. 36:953–954. 2014. View Article : Google Scholar : PubMed/NCBI

58 

Levéen P, Kotarsky H, Mörgelin M, Karikoski R, Elmér E and Fellman V: The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: A viable mouse model for mitochondrial hepatopathy. Hepatology. 53:437–447. 2011. View Article : Google Scholar : PubMed/NCBI

59 

Viscomi C, Spinazzola A, Maggioni M, Fernandez-Vizarra E, Massa V, Pagano C, Vettor R, Mora M and Zeviani M: Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice. Hum Mol Genet. 18:12–26. 2009. View Article : Google Scholar : PubMed/NCBI

60 

Dabrowska A, Tarnowska C, Jałowinski R, Stankiewicz J and Grzegorz M: Multiple symmetric lipomatosis in the otolaryngology as diagnostic and therapeutic problem. Otolaryngol Pol. 59:717–722. 2005.(In Polish). PubMed/NCBI

61 

Yoshida I, Sweetman L, Kulovich S, Nyhan WL and Robinson BH: Effect of lipoic acid in a patient with defective activity of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, and branched-chain keto acid dehydrogenase. Pediatr Res. 27:75–79. 1990. View Article : Google Scholar : PubMed/NCBI

62 

Uyama E, Kutsukake Y, Hara A, Uemura K, Uchino M, Mita S, Ando M and Taketomi T: Abnormal excretion of urinary phospholipids and sulfatide in patients with mitochondrial encephalomyopathies. Biochem Biophys Res Commun. 194:266–273. 1993. View Article : Google Scholar : PubMed/NCBI

63 

Doleris LM, Hill GS, Chedin P, Nochy D, Bellanne-Chantelot C, Hanslik T, Bedrossian J, Caillat-Zucman S, Cahen-Varsaux J and Bariety J: Focal segmental glomerulosclerosis associated with mitochondrial cytopathy. Kidney Int. 58:1851–1858. 2000. View Article : Google Scholar : PubMed/NCBI

64 

Menegon LF, Amaral TN and Gontijo JA: Renal sodium handling study in an atypical case of Bartter's syndrome associated with mitochondriopathy and sensorineural blindness. Ren Fail. 26:195–197. 2004. View Article : Google Scholar : PubMed/NCBI

65 

Valnot I, von Kleist-Retzow JC, Barrientos A, Gorbatyuk M, Taanman JW, Mehaye B, Rustin P, Tzagoloff A, Munnich A and Rötig A: A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency. Hum Mol Genet. 9:1245–1249. 2000. View Article : Google Scholar : PubMed/NCBI

66 

Imasawa T, Tanaka M, Yamaguchi Y, Nakazato T, Kitamura H and Nishimura M: 7501 T > A mitochondrial DNA variant in a patient with glomerulosclerosis. Ren Fail. 36:1461–1465. 2014. View Article : Google Scholar : PubMed/NCBI

67 

Kobayashi A, Goto Y, Nagata M and Yamaguchi Y: Granular swollen epithelial cells: A histologic and diagnostic marker for mitochondrial nephropathy. Am J Surg Pathol. 34:262–270. 2010. View Article : Google Scholar : PubMed/NCBI

68 

de Lonlay P, Valnot I, Barrientos A, Gorbatyuk M, Tzagoloff A, Taanman JW, Benayoun E, Chrétien D, Kadhom N, Lombès A, et al: A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat Genet. 29:57–60. 2001. View Article : Google Scholar : PubMed/NCBI

69 

Magner M, Dvorakova V, Tesarova M, Mazurova S, Hansikova H, Zahorec M, Brennerova K, Bzduch V, Spiegel R, Horovitz Y, et al: TMEM70 deficiency: Long-term outcome of 48 patients. J Inherit Metab Dis. 38:417–426. 2015. View Article : Google Scholar : PubMed/NCBI

70 

Riley LG, Rudinger-Thirion J, Schmitz-Abe K, Thorburn DR, Davis RL, Teo J, Arbuckle S, Cooper ST, Campagna DR, Frugier M, et al: LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure. JIMD Rep. 28:49–57. 2016. View Article : Google Scholar : PubMed/NCBI

71 

Saada A, Shaag A, Arnon S, Dolfin T, Miller C, Fuchs-Telem D, Lombes A and Elpeleg O: Antenatal mitochondrial disease caused by mitochondrial ribosomal protein (MRPS22) mutation. J Med Genet. 44:784–786. 2007. View Article : Google Scholar : PubMed/NCBI

72 

Tucker EJ, Wanschers BF, Szklarczyk R, Mountford HS, Wijeyeratne XW, van den Brand MA, Leenders AM, Rodenburg RJ, Reljić B, Compton AG, et al: Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression. PLoS Genet. 9:e10040342013. View Article : Google Scholar : PubMed/NCBI

73 

Gupta A, Colmenero I, Ragge NK, Blakely EL, He L, McFarland R, Taylor RW, Vogt J and Milford DV: Compound heterozygous RMND1 gene variants associated with chronic kidney disease, dilated cardiomyopathy and neurological involvement: A case report. BMC Res Notes. 9:3252016. View Article : Google Scholar : PubMed/NCBI

74 

D'Aco KE, Manno M, Clarke C, Ganesh J, Meyers KE and Sondheimer N: Mitochondrial tRNA(Phe) mutation as a cause of end-stage renal disease in childhood. Pediatr Nephrol. 28:515–519. 2013. View Article : Google Scholar : PubMed/NCBI

75 

Scaglia F, Vogel H, Hawkins EP, Vladutiu GD, Liu LL and Wong LJ: Novel homoplasmic mutation in the mitochondrial tRNATyr gene associated with atypical mitochondrial cytopathy presenting with focal segmental glomerulosclerosis. Am J Med Genet A. 123A:172–178. 2003. View Article : Google Scholar : PubMed/NCBI

76 

Matsumura M, Nakashima A, Araki T, Tofuku Y, Koizumi J, Yagi K, Koni I and Mabuchi H: L-Carnitine supplementation in a hemodialysis patient with a mutation in the mitochondrial tRNA(Leu(UUR)) gene. Nephron. 85:275–276. 2000. View Article : Google Scholar : PubMed/NCBI

77 

Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, Fang H, Song X, Cattran DC, Avila-Casado C, et al: ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest. 123:5179–5189. 2013. View Article : Google Scholar : PubMed/NCBI

78 

McDonald DG, McMenamin JB, Farrell MA, Droogan O and Green AJ: Familial childhood onset neuropathy and cirrhosis with the 4977bp mitochondrial DNA deletion. Am J Med Genet. 111:191–194. 2002. View Article : Google Scholar : PubMed/NCBI

79 

Broomfield A, Sweeney MG, Woodward CE, Fratter C, Morris AM, Leonard JV, Abulhoul L, Grunewald S, Clayton PT, Hanna MG, et al: Paediatric single mitochondrial DNA deletion disorders: An overlapping spectrum of disease. J Inherit Metab Dis. 38:445–457. 2015. View Article : Google Scholar : PubMed/NCBI

80 

Capková M, Tesarová M, Wenchich L, Cerná L, Hansíková H, Hůlková H, Hrubá E, Elleder M and Zeman J: Disorders of mitochondrial energy metabolism in patients with the Kearns-Sayre syndrome. Cas Lek Cesk. 141:51–54. 2002.(In Czech). PubMed/NCBI

81 

Löwik MM, Hol FA, Steenbergen EJ, Wetzels JF and van den Heuvel LP: Mitochondrial tRNALeu(UUR) mutation in a patient with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis. Nephrol Dial Transplant. 20:336–341. 2005. View Article : Google Scholar : PubMed/NCBI

82 

Tzen CY, Tsai JD, Wu TY, Chen BF, Chen ML, Lin SP and Chen SC: Tubulointerstitial nephritis associated with a novel mitochondrial point mutation. Kidney Int. 59:846–854. 2001. View Article : Google Scholar : PubMed/NCBI

83 

Tabebi M, Mkaouar-Rebai E, Mnif M, Kallabi F, Ben Mahmoud A, Ben Saad W, Charfi N, Keskes-Ammar L, Kamoun H, Abid M, et al: A novel mutation MT-COIII m.9267G>C and MT-COI m.5913G>A mutation in mitochondrial genes in a Tunisian family with maternally inherited diabetes and deafness (MIDD) associated with severe nephropathy. Biochem Biophys Res Commun. 459:353–360. 2015. View Article : Google Scholar : PubMed/NCBI

84 

Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chrétien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, et al: Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet. 39:776–780. 2007. View Article : Google Scholar : PubMed/NCBI

85 

Kanabus M, Shahni R, Saldanha JW, Murphy E, Plagnol V, Hoff WV, Heales S and Rahman S: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation. J Inherit Metab Dis. 38:211–219. 2015. View Article : Google Scholar : PubMed/NCBI

86 

Distelmaier F, Haack TB, Catarino CB, Gallenmüller C, Rodenburg RJ, Strom TM, Baertling F, Meitinger T, Mayatepek E, Prokisch H, et al: MRPL44 mutations cause a slowly progressive multisystem disease with childhood-onset hypertrophic cardiomyopathy. Neurogenetics. 16:319–323. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

May 2017
Volume 6 Issue 5

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Finsterer, J., & Finsterer, J. (2017). Renal manifestations of primary mitochondrial disorders (Review). Biomedical Reports, 6, 487-494. https://doi.org/10.3892/br.2017.892
MLA
Finsterer, J., Scorza, F."Renal manifestations of primary mitochondrial disorders (Review)". Biomedical Reports 6.5 (2017): 487-494.
Chicago
Finsterer, J., Scorza, F."Renal manifestations of primary mitochondrial disorders (Review)". Biomedical Reports 6, no. 5 (2017): 487-494. https://doi.org/10.3892/br.2017.892